The proposed research will investigate the mechanisms of negative inotropic action of various anesthetics. Different anesthetics depress myocardial contractility to different degrees. It is possible they may act on the heart by different mechanisms. We propose to study the effects of inhalation anesthetics on the Ca 2 ion activation of the contractile proteins and Ca 2 ion release from and uptake by the sarcoplasmic reticulum (SR). Using functionally skinned fiber preparations, the anesthetic effects on the intracellular sites and on mechanical contraction (tension) can be demonstrated simultaneously. Fiber bundles will be isolated from homogenized muscles from rabbits and will be fixed on a tension transducer. The skinned fiber preparation will be immersed in solutions containing specific ionic compositions. We will determine the anesthetic effects on Ca 2 ion binding the regulatory proteins and interactions of actin and myosin by measuring: (a) changes in submaximum Ca 2 ion activated tension at pCa equals 5.6 to 4.8 and (b) changes in maximum Ca 2 ion activated tension at pCa equals 4.0 to 3.4. We will establish the anesthetic effects on Ca 2 ion release from and uptake by SR by measuring changes in tension transients from caffeine-, Na ion-, Cl-, or Ca 2 ion induced Ca 2 ion release. The anesthetics to be studied are halothane, enflurane, isoflurane, nitrous oxide, and diethyl ether. Dose-response relationship of the anesthetics will be determined on the above mechanisms.